Editorial [ Hot Topic: Oncolytic Virus Therapy (Guest Editor: Hideki Kasuya) ]

At first, Dr. J. C. Bell states in this issue what we should now do for the next steps and the directions for the oncolytic virus therapy of the future. He emphasizes the importance of embracing the technology accumulated so far, and of using our understanding of the molecular biology of cancer and viruses for further breakthroughs. In the new era of oncolytic virus therapy, the environment is changing from early basic research to a large number of clinical trials. Actually some of them have yielded approval of a new drug in China for example. Oncolytic virus therapy is not a mere dream, with many suffering patients waiting for relief from cancer. About 10 years ago, the dramatic debut of G207 and Onyx-015 was a giant step in the field of cancer drug therapy. In 1996, the oncolytc adenovirus, Onyx-015, was submitted and filed in the Investigational Drug Section (IDS), and only 4 years later, in 2000, phase III trials were initiated. H101 is an added E3-deletion similar in design to ONXY-015. H101 entered phase III clinical trials in 2000 in China, and 5 years later, was approved by the Chinese FDA. It took only 9 years (1996 - 2005) for the oncolytic adenovirus to be approved as a new drug. This new drug, H101, mostly showed an anti-cancer effect in combination therapy with conventional chemotherapy drugs. Sunway Biotech in Shanghai showed the rate of tumor regression (CR+PR) as follows. H101 with chemotherapy : chemotherapy alone = 78.8% : 39.6% (p value = 0.000). An adenovirus has strong capacity to cause inflammation at the spot of injection. This inflammation reflex of adenovirus can exert a strong effect on among oncolytic viruses. At present, the immune response caused by an oncolytic virus seems to be one of the important anti-cancer activities in the human body. In this issue, Dr. H. Fukuhara and Dr. T. Todo write about the issue of host immune mechanism and “armed” oncolytic HSV-1 vectors using G47δ. A host body acquires the immune response through the change of cell surface viral antigen (MHC-I), and activated CD-8, NK cells would attack tumor cells including the oncolytic virus. Thus, the strong inflammation reflex caused by the oncolytic virus may be beneficial in triggering the subsequent host immune response. They indicate that virus “oncolysates” may be useful for cancer immunotherapy. However, the capacity to induce strong inflammation might imply a dangerous aspect, should excessive high titer virus be injected into the venous tract. We must not forget the tragedy of OTC-gene therapy, which occurred at the University of Pennsylvania. Systemic injection of oncolytic virus is another topic in this special issue about Vaccinia virus and Newcastle disease virus. The capacity for systemic injection includes the possibility of inhibiting distal micro-metastasis, and is very important for advanced cancer therapy. Dr. A. M. Crompton and Dr. D. H. Kirn describe the potential of Vaccinia virus for systemic injection; and Dr. R. M. Lorence presents a very interesting phenomenon dealing with the systemic injection of Newcastle disease virus that is related to the effect of high repeat doses, and a slower infusion rate for desensitization. Those technical improvements have numerous possibilities, and may well be effective for other types of oncolytic virus as well regarding systemic injection. We also deal in this issue with HF10 clinical trials in Japan. HF10 is attenuated herpes simplex virus type-1. We show the pathological changes, caused by HF10 oncolysis in tissues. The oncolytic virus itself has a great capacity for tumor cell lysis as shown in the photographs. In the next step, we hope to perform combination therapy of HF10 with chemotherapy drugs or radiation. Some papers have stated that combination therapy of herpes oncolytic virus was expected to increase virus replication, consecutive tumor regression and survival rate in an in vivo model, but other studies mentioned that both radiation and chemotherapy diminished viral replication. Comprehension of the time-length of viral replication in a tumor site is very important for the evaluation of the therapy. It is a very key to oncolytic viral therapy......